Endothelin is an endogenous physiologically active peptide consisting of 21 amino acids and it has been known that, in endothelin, there are three isopeptides of ET-1, ET-2 and ET-3 wherein the amino acid sequences are somewhat different.
Endothelin expresses its physiological action by binding to an endothelin receptor on a target cell membrane. For endothelin receptor, it has been clarified until now that there are at least two subtypes and those subtypes are named ET.sub.A and ET.sub.B, respectively. Those receptors differ in their affinity to endothelin. ET.sub.A receptor has a higher affinity to ET-1 and Et-2 than to ET-3 while ET.sub.B receptor has the affinity of a similar degree to the three types of endothelin.
Endothelin and endothelin receptor are produced and expressed, respectively, in various cells of various organs and varieties of physiological actions which are caused by them have been known. For example, in blood vessel, ET-1 which is produced and secreted in vascular endothelial cells bound ET.sub.A receptor on smooth muscle cells of blood vessel existing near there and contracts the blood vessel strongly and continuously. On the other hand, vascular endothelial cells themselves express ET.sub.B receptor and, when ET-1 is bonded thereto, nitrogen monoxide (NO) is produced and released. Nitrogen monoxide has an action of relaxing the smooth muscle of blood vessel. In fact, when ET-1 is intravenously injected to rat experimentally, long-lasting hypertension is observed after a transient hypotension.
As noted from the physiological action in blood vessel as mentioned above, ET-1 has an aspect as a physiologically active peptide having a very strong and continuous contraction to blood vessel and, because of that, its relation to diseases, particularly to cardiovascular diseases, has been discussed since the time when it was found.
Today, it is pointed out that there is a possibility that an excessive secretion of endothelin, particularly ET-1 (to be more specific, an increase in ET-1 concentration either topically or in tissues and circulating blood), participates not only in cardiovascular diseases but also in many other diseases. Thus, it was reported to participate, for example, in essential hypertension, pulmonary hypertension, hypertension induced by erythropoietin, hypertension induced by cyclosporin A, bronchial asthma, acute renal failure, chronic renal failure, glomerular nephritis, renal failure induced by cyclosporin, acute myocardial infarction, unstable angina, congestive heart failure, cerebrovascular spasm mostly after subarachnoid hemorrhage, cerebroischemic disturbance, urinary incontinence, benign prostatic hypertrophy, arteriosclerosis, Raynaud's syndrome, diabetic peripheral circulatory disturbance, diabetic renal diseases, preeclampsia, premature delivery, digestive ulcer, hepatic failure, rheumatism, restenosis after PTCA, chronic respiratory failure, chronic obstructive pulmonary diseases, cor pulmonale, acute respiratory failure, pulmonary edema, ischemic hepatic disturbance, adult respiratory distress syndrome, interstitial pneumonia, pulmonary fibrosis, glaucoma, osteoarthritis, chronic articular rheumatism, hepatic cirrhosis, inflammatory bowel diseases (IBD), cancer, etc. (G. M. Rubanyi, M. A. Plokoff, Pharmacological Reviews, vol. 46, no. 3, 325 (1994); Saishin Igaku, vol. 49, no.3, 335 (1994); Kidney International, 37, 1487-1491(1990); Lancet, 339, 381-385(1992); Cell Mol. Neurobiol., 13, 15-23 (1993); J. Clin. Encocrino. Metab., 76, 378-383 (1993); J. Clin. Pathol., 48(6), 519-524 (1995); Chest, 104(2), 476-480(1993); Am. J. Med., 99(3), 155-160 (1995); Hepatology, 16, 95-99 (1992); etc.).
Accordingly, pharmaceuticals which inhibit the binding of ET-1 to endothelin receptor by bonding to endothelin receptor, i.e. endothelin receptor antagonists, can be effective preventive and therapeutic agents to the diseases as mentioned hereinabove.
With regard to such endothelin receptor antagonists, a series of benzenesulfonamide derivatives is disclosed in the Japanese Laid-Open Patent Publications Hei-05/155,864, Hei-05/222,003, Hei-06/211,810 and Hei-07/017,972. In particular, a compound which is represented by the following formula ##STR2## which is disclosed in Example 67 of the Japanese Laid-Open Patent Publication Hei-05/222,003 (generic name: Bosentan) has been reported for its effectiveness and absorption by oral administration in pathogenic animal models (J. Pharmacol. Exp. Ther., 270(1), 228-2345, 1994; Hypertension, 224, 183-188, 1994; Clin. Pharmacol. Ther., 60, 124-137, 1996).